Pulmonary hypertension (PH) is a disease which involves vascular remodeling in the lung. We have recently described a novel gene product that is significantly increased during the chronic hypoxia model of PH, which we subsequently named hypoxia-induced mitogenic factor (HIMF). In mice, we have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, and chemokine-like properties in animal models of PH. We hypothesize that HIMF and its human counterparts promote vascular hypertrophy and hyperplasia, inflammation and abnormal vessel growth that will eventually lead to the development of PH. We will employ both animal and human models to better understand the role of HIMF in this process. Gain of function and loss of function experiments will be performed in animal models using HIMF-gene transfer and siRNA technologies. We will also evaluate human lung samples from idiopathic PH and scleroderma associated PH for expression of the human HIMF analogs, resistin and RELMbeta. Finally, we will study the cellular signaling associated with the proliferative response in both human lung vascular smooth muscle and endothelial cells. These studies will provide insights into the role of HIMF in the development of PH. [unreadable] [unreadable] [unreadable] [unreadable]